Several publications are referenced in this application by numerals in parentheses in order to more fully describe the state of the art to which this invention pertains. Full citations for these references are found at the end of the specification. Several patents and patent applications are also referenced in this application by number. The disclosure of each of these publications, patents, and patent applications is incorporated by reference herein.
Nearly twenty years have passed since the human immunodeficiency virus (HIV) was first identified as the causative agent of acquired immunodeficiency syndrome (AIDS). The human toll of this virus is tragic—almost 20 million people have died of AIDS, over 30 million are currently living with HIV, and 16,000 new infections occur daily. Still, there is neither a cure nor a proven therapy or vaccine for the treatment of HIV/AIDS.
Human immunodeficiency virus type-1 (HIV-1) infection is characterized by a host-virus relationship in which the virus utilizes the host cell's macromolecular machinery and energy supplies to produce progeny virus (1). Inevitably, after initial infection by HIV-1, the virus alters the host cell's physiological state, leading to disruption of immune responses, cell growth arrest and cell death (2). Specific viral and host cellular proteins are known to play crucial roles in this process (3). For example, the HIV-1 accessory proteins and host cell chemokine co-receptors, CCR5 and CXCR4, are essential for HIV-1 infection (4, 5, 6), and host cell target genes such as Ets-1, CDK4, NFAT1 and NFAT2, induce enhanced HIV-1 gene expression in vitro (7-11).
HIV-1 preferentially infects a class of immune cells called CD4+ T cells or helper T cells which are essential to the function of the immune system. Following primary HIV-1 infection, the virus replicates in local lymph nodes and then disseminates in a massive viremia. Although HIV-1 elicits strong immune responses in most infected individuals, the virus almost invariably escapes immune containment (1, 2). Persistent HIV-1 infection is further characterized by a gradual decrease in CD4+ T cells which leads to AIDS and ultimately death.
Analyses of T cells from individuals infected with HIV-1, or of T cells infected in vitro with HIV-1, indicate that a significant fraction of both infected and uninfected cells undergo programmed cell death or apoptosis. Apoptosis is a regulated form of cellular suicide that is critical to many physiological processes, including T cell development and normal immune function. However, the mechanisms of apoptosis in HIV-1 infection remain obscure and controversial. Analyses of lymphoid tissues from HIV-1 infected humans and SIV-1 (simian immunodeficiency virus) infected macaques suggest that most infected cells are not apoptotic and that the majority of apoptosis occurs in uninfected bystander cells (12). These data suggest that HIV-1 infected cells in vivo are relatively protected from or resistant to apoptosis.
Current therapies against HIV-1 infection are specific for targeting the virus. However, these therapies are not able to induce sustained suppression or cure of HIV because of HIV's ability to develop resistance to the treatment. Even when the amount of virus in the blood falls below the current limits of detection, HIV continues to reproduce at very low levels or alternatively, resides in a “reservoir” of latently infected T cells.
One treatment for HIV-1 infection is a cocktail of anti-viral drugs known as Highly Active Anti-Retroviral Therapy (or HAART) which includes two reverse transcriptase inhibitors and a protease inhibitor. HAART reduces the viral load in many patients to levels below the current limits of detection, but the rapid mutation rate of this virus limits the efficacy of this therapy (13). In addition, HAART is ineffective in some patients with HIV-1 infection and many more cannot tolerate its debilitating side effects.
Therapies for HIV-1 infection in the experimental stages of testing include the development of vaccines against HIV-1. Vaccines based on engineered gp120-CD4-CCR5 fusion proteins have been shown to elicit antibodies capable of neutralizing HIV-1 infectivity (14). Moreover, evidence of in vivo efficacy is not yet available and most researchers believe that a highly promising ideal vaccine candidate is not yet at hand (15).
Given the continuing impact of the HIV epidemic around the world and the lack of a proven therapy which provides sustained protection against HIV infection and AIDS, there remains a critical need for HIV research to identify new ways to prevent and treat this deadly disease.